17alpha-lower alkyl, 17alpha-lower alkinyl and 17alpha-lower alkenyl derivatives of 19-nor-delta5-androsten-17beta-ol-3-one



United States Patent net-rowan ALKYL, 17oc- LOWER ALKINYL AND Hot-LOWER ALKENYL DERIVATIVES or 19- NOR-M-ANDROSTEN-17,8-0L-3-0NE Carl Djerassi and 'Jos Iriarte, Mexico City, Mexico, as-

The present invention relates to cyclopentanophenan: threne compounds and to a process for the production thereof.

More particularly the present invention relates to 170:- lower alkyl, lower alkinyl and lower alkenyl derivatives of 19-nor-A -androsten-17,8-01-3-one and to a process for the production of these compounds. The novel 17a-lower alkyl, lower alkinyl and lower alkenyl derivatives (including their esters as hereinafter set forth) of 19-nor-A androsten-l7fi-ol-3-one are all novel progestational hormones. In addition the 170L-1OWCI alkyl and 17a-1OW61 alkinyl derivatives and their esters have a pronounced anabolic activity.

In U.S. application Serial No. 727,523 of Bowers, Ringold, and Rosenkranz, filed April 10, 1958, now abandoned, there is disclosed novel 17oz-1OWBI' alkyl, lower alkinyl and lower alkenyl derivatives of l9-nor-A -androstem-35,17fl-diol, esters thereof and a process for the production thereof.

In accordance with the present invention the surprising discovery has been made that these compounds may be selectively oxidized at the 3-position to give the corresponding 3-ketones of the present invention without the migration of the double bond between 0-5 and C-6 to the position between 0-4 and C5 in conjugation with the keto group at C-3.

The novel compounds of the present invention are illustrated by the following formula:

In the above formula R represents lower alkyl, i.e., an alkyl group of less than 7 carbon atoms such as methyl, ethyl, propyl or butyl or R represents lower alkinyl, i.e., an alkinyl group of 2 to 6 carbon atoms such as ethinyl, propinyl-( 1) or butinyl-(l) or R represents lower alkenyl, i.e., an alkenyl group of 2 to 6 carbon atoms such as vinyl, propenyl-(l), or butenyl-( 1). R represents hydrogen or R may represent an acyl group of a hydrocarbon carboxylic acid of up to 12 carbon atoms. The hydrocarbon carboxylic acyl groups referred to above are those conventionally used in the art in the esterification of steroid alcohols and as is known may be straight or branched chain, aliphatic, cyclic or mixed cyclic-aliphatic. They may be substituted with groups such as halogen or methoxy. Typical ester groups are acetate, propionate, butyrate, hemisuccinate, caproate, benzoate, trimethylacetate, phenoxyacetate, phenoxypropionate, pentylpropionate,

3,145,221 Patented Aug. 187, 1964 cyclopentylpropionate, dichlorophenoxyacetate, and chloropropionate.

The novel compounds set forth above are produced by a novel process illustrated by the following equation:

OR OR In the above equation R and R represent the same groups as hereinbefore set forth.

In practicing the novel process above outlined, the lower alkyl, lower alkinyl or lower alkenyl derivative of 19 nor A androsten-35,17B-diol or the 17-monoesters thereof of the type above set forth are dissolved in a lower aliphatic ketone solvent such as acetone or methyl ethyl ketone, cooled to a temperature between 0 and 10 C. and treated under nitrogen with chromic acid while maintaining the aforesaid low temperature. The chromic acid is quickly added and the reaction mixture is kept at the aforementioned low temperature for a period of time of 2 to 5 minutes. Upon extraction with organic solvent such as ether, washing with water, drying, filtration and evaporation, there is obtained the corresponding 17u-substituted 19-nor A androsten ol-3-one compound. The pure substances may be obtained by conventional chromatography on silica gel.

The following specific examples serve to illustrate but are not intended to limit the present invention.

Example I order to replace the air in the apparatus for nitrogen.

There was then quickly added, always under nitrogen and with stirring, an 8 N solution of chromic acid, while the temperature was maintained at around 5 C.; there was added enough 8 N chromic acid until the yellow color of chromium trioxide persisted in the mixture, which was then kept at 5 C. for 3 minutes more. The mixture was extracted with ether and the extract was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crystalline residue consisted of 17tx-ethinyl-l9-nor-A -androsten-17 3-01- 3-one.

By chromatography on silica gel there was obtained the pure substance, M.P. 143-145 C. In the ultraviolet spectrum the substance only shows a minor absorption in the region between 220 and 290 me; however, upon treatment with a small amount ofv alkali, for example with a few drops of methanolic potassium hydroxide, a maximum developed at 240 m with a molecular extinction coeflicient (log E) of 4.2, which maximum is characteristic of a A -3-ketone and indicates the migration of the double bond to A through the action of the alkali.

Example II By the same method described in Example I, there was oxidized 200 mg. of 17a-ethinyl-l9-nor-A -androsten-3B,

17 341101 17-acetate to form 17a-ethinyl-19-nor-A -androsten-17 3-ol-3-one 17-acetate, which practically showed no selective absorption in the ultraviolet spectrum.

Example 111 Following the method of Example I, 500 mg. of 170L- methyl-l9-nor-A -androsten-3fi,17fi-diol, dissolved in 250 cc. of acetone, was oxidized by reaction with 8 N chromic acid to produce the crude 17a-methyl-l9-r1or-A -androsten-17fl-ol-3-one with M1. 134138 C. By chromatography on silica gel there was obtained the pure substance, M.P. 139-140 C., which showed no selective absorption in the ultraviolet spectrum.

Example IV Following the method of Example I, there were prepared from the starting materials indicated below the final products indicated below:

Starting Material Product The 17-mononcetate of 17 n-methyl- 19-n0r-A -androsten-3B, 17,9-(1101.

The 17-monoacetate of 17 u-vinyl- 19-n0r-A -andrsten-3fl 175-6101.

The 17-m0noncetate of 1 -ethyl-19- nor-A -androsten-3fi, 176-11101.

The l7-monoacetate of 17 a-propiny1-(1)-19-nor-A androsten- 35, 11541101.

The 17-monoz1cetate of l7a-propenyl-(l)JQ-nQr-M-tandrosten- 35, 17541101.

The 17-monoaeetate of Uri-propyl- 19-nor-A -androsten-3fi, 17541101.

The 17-monoacetate of17a-butiny1- ((11) -11 9-110r-A -a11d1'0sten-3fi, 1718- The 17-monoaeetate 0f17a-buteny1- The 17-monoacetate of 17 a-butyl- 19-n0r-A -androsten-3fl-17B-diol.

The 17-monopropionate of 17 0.-

methyl-19mm-A -andr0sten-3fi, 17541101.

The 17-monopropionate of 17 vinyl-lQ-nor-N-androsten-3fi, 175-(1101.

The l7-m0nopropionate of 17 gthlyl-l -nor-A -androsten-3fl- 176- The 17-monoprop1onate of 17 a-propinyl-(11-19-110r-A -androsten-3fl, 17fl-diol.

The 17-m0n0prop1onate of 17 a.-p1'O- penyl-(l)-19-nor-A -androsten-3B, 17B-d1o1.

The 17-monopr0p1onate of 17 a-pro- 5 1-19-110r-A -a11drosten-3;3, 17B- 10 The 17-monoacetate of 17 a-methy 1tl-nor-A -androsten-17B-0l-3-ene.

The 17-monoacetate of 17 methyl-19 nor-M-androsten-17fl-0l-3-one.

The 17-m0r1oacete1e 0i 17u-propinyl-(l)-19-n0r-A -andr0sten- 17501-30110.

The 17-monoacetate oi viz-propyl- 1Q-nOr-N-androsten-17fi-o1-3-0ne.-

The 17-monoacetate of 17a-b11tlnyl (1) -19-nor-A -androsten-17fi-o1-3- one.

The 17-monoacetate of 17 a-butenyl- (1) -l9-D0X-A -3l1dr0S1911-175-013- one.

The 17-monoacetate of lia-butyl- 19-n0r-A -androsten-17flbl-3-one.

The 17-monoprop1onate of 1711- methyl-IQ-nor-A -endr0ste11-17B, o1-3-0ne.

The 17-monopropionate of 17 avinyl-ltl-nor-A -andr0sten-17fl-ol- 3-one.

The 17-monopropionate 01 17 aethyl-lfl-nor-N-nndrosten-ITfl-ol- 3-one.

The 17-monopropionate of 17 a-propinyl-(l)-19-n0r-A -andr0sten-l7fl- 01-30110.

The 17-monopropionate of 17 a-pro- Starting Material Product The 17-mor1opr0p1onate of 17a.- The 17-monopropionate 0117a- The 17-monopropi0nate of 17a.-

butenyl-( 1) -19-n0r-A -andr0sten- 3e, 17B-diol.

The l7-monopropionate of 17 a.-

butyl-ltl-nor-A -andr0sten-3fi, 171841101.

1 0 17 a-vin yl-19-nor-A -androsten-3B,

17 a-butenyl-(l) -19-nor-A -androemu-3e, 17541101.

17 a-buty1-19-n0r-A -androsten-3B,

Example V When in the methods of the prior examples other 17- mono esters of the 17a-alkyl, alkinyl or alkenyl deriva- References Cited in the file of this patent UNITED STATES PATENTS 2,813,880 Campbell et a1. Nov. 19, 1957 2,833,794 Goldkamp et a1. May 6, 1958 2,838,530 Colton June 10, 1958 2,888,468 Djerassi et al. May 26, 1959 OTHER REFERENCES Chemical Abstracts, vol. 51, Subject Index Issue," December 25, 1957, p. 917s.

Iriarte et al.: J. Am. Chem. Soc., vol. 81, January 20, 1959, pp. 436-438. 

